Fight Aging!

One of the important points made by advocates for the treatment of aging is that one cannot distinguish between aging and age-related disease. They are one and the same. There is no magical state of "healthy aging" in which one doesn't suffer eventual disease. A decline of function in aging that does not rise to the level required to call it a disease is the subclinical stage of that disease; all the same damage has taken place under the hood, just less of it. Conversely, an age-related disease is just another facet of aging, a collection of damage and consequences of damage that becomes sizable enough to reach the definition of disease. Whether or not any specific age-related dysfunction is called a disease is just a matter of whether the degree of dysfunction is on one side or another of an arbitrary line drawn in the sand.

The authors of today's open access paper take this point and then build on it to suggest that the most robust age-slowing approaches demonstrated in animal models should be tested more rigorously in patients with common, hard-to-treat conditions such as Alzheimer's disease. The approaches with the best data include calorie restriction and all of the calorie restriction mimetic interventions that seek to replicate some part of the sweeping cellular reaction to a reduced intake of calories. Interestingly, this hasn't been well tested in Alzheimer's patients. Perhaps it should be, even given that the research community expects effects on aging to be lower in long-lived species than in short-lived species. While calorie restriction extends mouse life span by as much as 40%, it certainly doesn't do that well in humans. The actual number has yet to be established, but it would be surprising to see that the effect of long-term calorie restriction or equivalent intermittent fasting in humans is larger than a few years of additional life span.

Aging as a target for the prevention and treatment of Alzheimer's disease

Alzheimer's disease (AD), the most common etiology of dementia in older adults, is projected to double in prevalence over the next few decades. Current treatments for AD manage symptoms or slow progressive decline, but are accompanied by significant inconvenience, risk, and cost. Thus, a better understanding of the risk factors and pathophysiology of AD is needed to develop novel prevention and treatment strategies.

While a mayfly has a lifespan of one day, an elephant's lifespan may exceed 100 years. Clearly, lifespan and aging are biological traits regulated by genetics and molecular signaling pathways - that may be exploited as a therapeutic target. Aging, however, is not recognized as a disease by the U.S. Food and Drug Administration. Thus, there are no FDA-approved treatments specifically for aging. Aging, however, is the most important risk factor for multiple diseases, including dementia and AD. As molecular mechanisms regulating aging are coming to light and signaling pathways uncovered, novel therapeutic targets present an alternative approach: instead of targeting one disease at a time - leading to the inconvenience, cost, and risk of polypharmacy - targeting aging directly may prevent or slow multiple age-related diseases. CR may be a promising preventive or therapeutic option for individuals at risk for AD or already within the AD spectrum. However, current data are limited and human studies are scarce. Additional preclinical and human studies are now warranted to discover the pathways regulated by CR and to identify pharmacophores that mimic the beneficial effects of CR.

Hypotheses linking CR and weight loss to alterations in biomarkers of aging and AD may suggest novel treatment targets and strategies-and not just for AD. Newly discovered therapies may be safe and effective for prevention and/or as an adjunct to FDA-approved treatments for individuals in the AD spectrum. Prevention and treatment strategies targeting aging may be safer and more effective than the currently available treatments targeting more downstream pathways. While several studies are in progress (listed above), more are needed. In the meantime, AD trials should consider including biomarkers of aging and aging studies should include AD biomarkers.

Microglia are innate immune cells resident in the brain, analogous to macrophages elsewhere in the body, but with the addition of a portfolio of duties relating to the maintenance of neural function. With age ever more microglia become overly inflammatory, contributing to disruptive, unresolved inflammatory signaling, and abandoning their tissue maintenance tasks. This is thought to be an important contribution to neurodegenerative conditions and loss of cognitive function more generally. Researchers here report that the adoption of an inflammatory state is a progressive dysfunction for individual microglia, not just a matter of how many microglia have switched over to undertake inflammatory behavior.

Numerous studies have indicated that aged microglia are inflamed, have reduced phagocytic capacity, and have decreased motility. Microglia exhibit several hallmarks of aging that potentially contribute to their age-related dysfunction, such as shortened telomeres, altered intercellular communication, molecular alterations, and a loss of proteostasis. Furthermore, many recent studies have started to reveal the molecular changes that define microglial aging. Single cell RNA-Seq (scRNA-Seq) analyses indicate that microglia isolated from the entire brain lose homeostasis and activate inflammatory transcriptional profiles with age. Data rich studies have also revealed partial overlaps between aging microglia and those from disease models, including Alzheimer's disease.

Studies using aged plasma administration and heterochronic blood exchange demonstrate that microglia aging is in part driven by the aged systemic environment. However, the genesis of age-related dystrophic microglial phenotypes has not been extensively investigated. So, we set out to characterize the progression of age-related hippocampal microglial dysfunction, aiming to uncover intermediate states that could be intrinsic to the aging process. To do so, we undertook complementary cellular and molecular analyses of microglia across the adult lifespan and in heterochronic parabiosis - an experimental model of aging in which the circulatory systems of young adult and aged animals are joined.

In this study, we report that microglia in the adult mouse hippocampus, a brain region responsible for learning and memory and susceptible to age-related cognitive decline, advance through intermediate states that drive inflammatory activation during aging. We utilize scRNA-Seq across the adult lifespan to identify intermediate transcriptional states of microglial aging that emerge following exposure to an aged systemic environment. Functionally, we tested the role of these intermediate states using in vitro microglia approaches and an in vivo temporally controlled adult microglia-specific Tgfb1 conditional genetic knockout mouse model to demonstrate that intermediates represent checkpoints in the progression of microglia from homeostasis to inflammatory activation, with functional implications for hippocampal-dependent cognitive decline.

Link: https://doi.org/10.1101/2024.04.09.588665

As an atherosclerotic plaque grows into a hotspot of inflammation and cell dysfunction in a blood vessel wall, it starts to draw in the nearby vascular smooth muscle cells that wrap the outside of the vessel. As researchers here note, these smooth muscle cells are altered by the plaque environment in ways that are analogous to the behavior of cancerous cells. They change, multiply, and accelerate the growth of a fatty plaque that will eventually rupture to cause a stroke or heart attack by blocking a downstream blood vessel.

Atherosclerosis is the major cause of heart attacks and stroke around the world and occurs when fat deposits build up inside the arteries. Atherosclerosis can be reduced with a healthy diet or drugs called statins that slow or reverse the buildup of deposits. Previous studies had found that smooth muscle cells metamorphose into different types of cells inside these atherosclerotic plaques and multiply to make up most cells within the plaques. Yet until now, few studies had examined the cancer-like properties of the cells and if these changes contributed to atherosclerosis. To learn more, researchers closely tracked the development of transformed smooth muscle cells in mice with atherosclerosis and sampled plaques of people with atherosclerosis. They found striking parallels between changes in the smooth muscle cells and tumor cells, including hyperproliferation, resistance to cell death, and invasiveness.

DNA damage, another hallmark of cancer, accumulated in the mouse and human smooth muscle cells and appears to accelerate atherosclerosis, the researchers found. The researchers could further accelerate atherosclerosis in mice by introducing a genetic mutation that increased DNA damage within the smooth muscle cells. Vascular tissue from healthy mice and people had no signs of smooth muscle cells with the DNA damage found in atherosclerotic plaques. "The cells stay inside existing plaques, which makes us think that they behave mostly like benign tumor cells, but more work needs to be done in humans and animal models to address this hypothesis." If atherosclerosis is driven by cancer-like cells, anticancer therapies may be a potential new way to treat or prevent the disease.

Link: https://www.eurekalert.org/news-releases/1043152

Chronic, unresolved inflammation is a feature of aging. When the immune system is constantly active in this way, the consequent altered cell behavior throughout the body becomes disruptive to tissue and organ function, harmful to the individual. Chronic inflammation accelerates the onset and progression of all of the common fatal age-related conditions. This unwanted inflammatory signaling arises from many different roots, including the growing presence of senescent cells, but also the interaction of innate immune sensors with other forms of age-related dysfunction. For example, damage-associated molecular patterns such as mislocalized fragments of mitochondrial DNA leaking from dysfunctional mitochondria into the cell cytosol can trigger cGAS/STING signaling. This mechanism evolved to detect the presence of bacterial DNA, and unfortunately runs awry with age.

The challenge inherent in dampening age-related chronic inflammation is that, so far, it appears to use exactly the same pathways that are involved in the normal, necessary, short-term inflammatory response to injury, pathogens, potentially cancerous cells, and so forth. All of the approaches developed to date to suppress the overactivity of an immune system also suppress necessary functions, and that produces unpleasant long-term consequences. This is well established via the use of immunosuppressant drugs in patients with autoimmune disease. There was some hope that targeting aspects of cGAS/STING function would prove to be a better option, but as researchers note in today's open access paper, an operating cGAS/STING pathway appears to be necessary for long-term health.

STING promotes homeostatic maintenance of tissues and confers longevity with aging

Local immune processes within aging tissues are a significant driver of aging associated dysfunction, but tissue-autonomous pathways and cell types that modulate these responses remain poorly characterized. The cytosolic DNA sensing pathway, acting through cyclic GMP-AMP synthase (cGAS) and Stimulator of Interferon Genes (STING), is broadly expressed in tissues, and is poised to regulate local type I interferon (IFN-I)-dependent and independent inflammatory processes within tissues. Recent studies suggest that the cGAS/STING pathway may drive pathology in various in vitro and in vivo models of accelerated aging.

To date, however, the role of the cGAS/STING pathway in physiological aging processes, in the absence of genetic drivers, has remained unexplored. This remains a relevant gap, as STING is ubiquitously expressed, implicated in multitudinous disorders, and loss of function polymorphisms of STING are highly prevalent in the human population (an incidence of more than 50%). Here we reveal that, during physiological aging, STING-deficiency leads to a significant shortening of murine lifespan, increased pro-inflammatory serum cytokines and tissue infiltrates, as well as salient changes in histological composition and organization.

We note that aging hearts, livers, and kidneys express distinct subsets of inflammatory, interferon-stimulated gene (ISG), and senescence genes, collectively comprising an immune fingerprint for each tissue. These distinctive patterns are largely imprinted by tissue-specific stromal and myeloid cells. Using cellular interaction network analyses, immunofluorescence, and histopathology data, we show that these immune fingerprints shape the tissue architecture and the landscape of cell-cell interactions in aging tissues. These age-associated immune fingerprints are grossly dysregulated with STING-deficiency, with key genes that define aging STING-sufficient tissues greatly diminished in the absence of STING. This altered homeostasis in aging STING-deficient tissues is associated with a cross-tissue loss of homeostatic tissue-resident macrophage (TRM) populations in these tissues. Ex vivo analyses reveal that basal STING- signaling limits the susceptibility of TRMs to death-inducing stimuli and determines their in situ localization in tissue niches, thereby promoting tissue homeostasis.

Collectively, these data upend the paradigm that cGAS/STING signaling is primarily pathological in aging and instead indicate that basal STING signaling sustains tissue function and supports organismal longevity. Critically, our study urges caution in the indiscriminate targeting of these pathways, which may result in unpredictable and pathological consequences for health during aging.

Dasatinib and quercetin used in combination clears a fraction of lingering senescent cells in aging mice, producing a sizable degree of rejuvenation, and reversal of aspects of many different age-related conditions. In humans, clinical trials are underway at a sedate pace. Dasatinib is a chemotherapeutic small molecule, while quercetin is a plant extract flavonol. Here, researchers discuss their search for plant extract alternatives that mimic the effects of dasatinib, in the hopes of producing a less regulated alternative to the use of a small molecule drug, thereby lowering the barrier to entry somewhat. Size of effect is important, however, and it is yet to be demonstrated that any of their proposed alternatives can replicate the degree to which dasatinib impacts senescent cells.

The major risk factor for chronic disease is chronological age, and age-related chronic diseases account for the majority of deaths worldwide. Targeting senescent cells that accumulate in disease-related tissues presents a strategy to reduce disease burden and to increase healthspan. The senolytic combination of the tyrosine-kinase inhibitor dasatinib and the flavonol quercetin is frequently used in clinical trials aiming to eliminate senescent cells.

Here, our goal was to computationally identify natural senotherapeutic repurposing candidates that may substitute dasatinib based on their similarity in gene expression effects. The natural senolytic piperlongumine (a compound found in long pepper), and the natural senomorphics parthenolide, phloretin, and curcumin (found in various edible plants) were identified as potential substitutes of dasatinib. The gene expression changes underlying the repositioning highlight apoptosis-related genes and pathways. The four compounds, and in particular the top-runner piperlongumine, may be combined with quercetin to obtain natural formulas emulating the dasatinib + quercetin formula.

Link: https://doi.org/10.1038/s41598-024-55870-4

Researchers have found evidence of cellular senescence in neurons in the aging brain. How do neurons become senescent, given that they are post-mitotic, non-dividing cells? Cellular senescence is state primarily associated with excessive cell division, in which a cell reaches the Hayflick limit, though cells can become senescent in response to damage or toxicity. Here, researchers provide evidence to show that in the aging brain, and particularly in the context of neurodegenerative conditions, ever more neurons re-enter the cell cycle, which inevitably leads to senescence. This is an interesting line of research, adding another argument for the use of senolytic drugs to treat neurodegenerative conditions.

Increasing evidence indicates that terminally differentiated neurons in the brain may recommit to a cell cycle-like process during neuronal aging and under disease conditions. Because of the rare existence and random localization of these cells in the brain, their molecular profiles and disease-specific heterogeneities remain unclear. Through a bioinformatics approach that allows integrated analyses of multiple single-nucleus transcriptome datasets from human brain samples, these rare cell populations were identified and selected for further characterization.

Our analyses indicated that these cell cycle-related events occur predominantly in excitatory neurons and that cellular senescence is likely their immediate terminal fate. Quantitatively, the number of cell cycle re-engaging and senescent neurons decreased during the normal brain aging process, but in the context of late-onset Alzheimer's disease (AD), these cells accumulate instead. Transcriptomic profiling of these cells suggested that disease-specific differences were predominantly tied to the early stage of the senescence process, revealing that these cells presented more proinflammatory, metabolically deregulated, and pathology-associated signatures in disease-affected brains. Similarly, these general features of cell cycle re-engaging neurons were also observed in a subpopulation of dopaminergic neurons identified in the Parkinson's disease (PD)-Lewy body dementia (LBD) model.

An extended analysis conducted in a mouse model of brain aging further validated the ability of this bioinformatics approach to determine the robust relationship between the cell cycle and senescence processes in neurons in this cross-species setting.

Link: https://doi.org/10.1371/journal.pbio.3002559

Transdifferentiation is the use of various techniques to convert a somatic cell of one type directly into a somatic cell of another type. This is an alternative to first using Yamanaka factors to dedifferentiate somatic cells into induced pluripotent stem cells, then guiding differentiation into the desired final somatic cell type. For both differentiation from pluripotency to somatic cell and transdifferentiation between somatic cells, a suitable recipe of factors and altered gene expression must be discovered for any given destination. A few of these protocols are now well known, but the vast majority have yet to be robustly established, or even attempted at all.

In today's open access paper, researchers refer to transdifferentiation as direct reprogramming, not to be confused with the various forms of reprogramming via Yamanaka factors, either to produce induced pluripotent stem cells, or to restore youthful epigenetic patterns via what is known as partial reprogramming or epigenetic reprogramming. Transdifferentiation offers the potential to treat aspects of aging and age-related disease that involve the loss of small, specific cell populations, such as dopaminergenic neurons or sensory hair cells. These critical populations are surrounded by other, more numerous, less critical cells, which might be targets for transdifferentiation given a sufficiently selective therapy. Proof of concept in these and a few other cases has been achieved in animal studies, and it remains to be seen as to how rapidly this can advance to the clinic.

Next-generation direct reprogramming

While the concept that mature cell states are stable holds the key for homeostasis of an organism, the long-held believe was that this state cannot ever be reversed. This fallacy has gradually broken down. Now, the Yamanaka factors are now widely used not only for reprogramming but also for partial reprogramming that leads to rejuvenation of tissues. Yet another kind of reprogramming was emerging from the basic science field, now dubbed direct reprogramming, or transdifferentiation (we use the terms interchangeably from here on). During transdifferentiation a differentiated cell changes its fate to another, more desired differentiated cell type, without entering a pluripotent stage. The first identified transcription factor capable of directly reprogramming fibroblasts to skeletal muscles was MyoD. Many other lineage-specific transcription factors capable of transdifferentiating a target cell have since been identified.

Whether induced or endogenous process, in general, pioneer factors (PF) act as the first responders in direct reprogramming by binding and opening closed chromatin. It is not clear if each transdifferentiation lineage is regulated by a specific pioneer factor, or if a universal PF for transdifferentiation (capable of initiating multitude of direct lineage reversions) is still to be identified. Transdifferentiation studies have unveiled the opportunities and offer applications in regenerative therapies, such as cell replacement therapy or immunotherapy. The key question, and the topic of this review is to identify new, feasible methods to induce specific, high efficiency and targeted transdifferentiation.

These next-generation transdifferentiation approaches will come with better efficiency and plausibly with potential to treat diseases like Alzheimer's disease, muscle injury, diabetes, or myocardial infarction, resulting in elimination of the unsurmountable treatment issues at the moment (for example, finding a right donor or graft rejections). These novel approaches will enhance the efficacy and safety of direct reprogramming, allowing the ultimate decoding of the process towards plausibly resulting in 21st century personalized regenerative medicine.

Both cancer and aging impair the activity of T cells of the adaptive immune system, forcing these cells into exhaustion and senescence. The state of exhaustion is incompletely understood, but appears as an issue in immunotherapies making use of engineered T cells, as well as in the natural population of the aged body. Since researchers are already altering the T cells used in cancer therapies, why not alter them further to make them more able to resist the effects of aging cancer on T cell populations in the body? This is an interesting and plausible goal, but one that requires a greater understanding of T cell exhaustion than presently exists.

Cellular immunotherapy is revolutionizing oncology by harnessing T cells' unique ability to specifically target and potentially cure metastatic cancer, a feat not achievable with traditional treatments. Living T cells have proven they can eradicate even the most stubborn metastatic cells. However, challenges persist, as these therapies sometimes fail when T cells do not endure, often succumbing to exhaustion or senescence. This issue is being addressed by researchers who are exploring methods to enhance T cell resilience and functionality.

Evolution has shaped T cells to occasionally dampen their function in chronic viral infections to prevent autoimmunity and mitigate potential harm from an overly aggressive immune response. For example, the immune system's complete elimination of a hepatitis virus could cause significant liver damage. Chronic activation can also drive T cells toward senescence and exhaustion, weakening the immune response to cancer. To address these challenges, researchers have developed checkpoint inhibitors and engineered T cells to create synthetic T cells that can reverse or bypass these evolutionary constraints with great success in some indications.

Researchers have developed a synthetic T cell state they call TIF (T cells with an immortal-like and functional state). TIF cells are the product of disrupting the BCOR and ZC3H12A genes, a result that is surprising because these genes are typically expressed at low levels in T cells and lack dynamic regulation. This approach is aimed at addressing the traditional trade-off in T cell therapies between longevity and potency, offering cells that not only persist longer but also retain robust anti-tumor capabilities. TIF cells demonstrate enhanced survival and can enter a reversible dormant state, like memory cells, providing long-term immunity. Without BCOR, and in combination with ZC3H12A deficiency, genes that are usually repressed might become active, enhancing both stemness- and cytotoxicity-associated genes. This could potentially remove brakes on the T cell stemness and cytotoxic programs, enhancing therapeutic efficacy.

Link: https://doi.org/10.1084/jem.20240258

Here find an open access review of the present landscape of biomarkers of aging, both single measures and composite measures of various sorts, such as the aging clocks developed over the past fifteen years. The development of a good, consensus measure of biological age would accelerate efforts to treat aging as a medical condition, as assessing the ability of various classes of treatment to slow or reverse aging is at present a slow and expensive process - the only proven approach is a life span study. Unfortunately, all present approaches to the assessment of biological age have their challenges. The accumulation of large amounts of data for analysis proceeds in parallel with the development of better aging clocks that seek to address the known issues.

One major barrier to longevity research is evaluating the impact of interventions that improve human health and longevity because they are complex processes that occur over long time scales. Instead, measurable phenotypic traits or proxies of longevity, termed longevity biomarkers, may be used to assess the effectiveness of longevity interventions, or prognosticate clinical outcomes. Longevity biomarkers are critical tools for predicting lifespan and susceptibility to age-related diseases, but there exist a dizzying array of options, with at times contradictory readouts, and other key weaknesses.

Strengths of longevity biomarkers include providing insight into an individual's biological age, as opposed to chronological age, which is pivotal in evaluating targeted interventions that address aging and age-related conditions. However, most longevity biomarkers also exhibit notable weaknesses, such as a lack of specificity and lack of standardization across different studies and applications. These weaknesses underscore the need for more research to enhance their accuracy and reliability in long-term longitudinal studies.

In the present review, we discuss key strengths and weaknesses of popular clinical biomarkers used to predict morbidity and mortality associated with advanced age, identify existing bottlenecks, and integrate the field consensus on further directions for robust lifespan and healthspan estimation.

Link: https://doi.org/10.55277/ResearchHub.dxewpyv0

There are many different ways to conceptualize programs of research and development aimed at the treatment of aging. The Strategies for Engineered Negligible Senescence (SENS) is focused on aging as damage accumulation, and treatment is thus damage repair: remove senescent cells, restore mitochondrial function, clear out harmful protein aggregates, and so forth. Programmed aging viewpoints instead focus on ways to alter what are suspected to be evolved programs that drive aging, with this line of thought most often centered around the reversal of epigenetic changes that are observed to occur with age.

In today's open access paper, the authors propose a viewpoint that they call juventology, the study of youth, in analogy to gerontology, the study of aging. Clearly calorie restriction and related interventions adjust the operation of metabolism to slow aging and prolong the period of youthful life in many species. This might be taken as the existence of youth-maintaining programs, a delay of aging programs, or a slowing of damage accumulation. People tend to see their own view of aging reflected in the data for calorie restriction. It causes such a broad set of changes in cellular biochemistry, where that biochemistry is itself not fully mapped, that it is hard to mount arguments in support of one theory of aging versus another.

Is this really a good choice of strategy, however? Do we believe that calorie restriction is a starting point for a field that will in time engineer some form of altered metabolism that is far more effective when it comes to prolonging youthful life? In principle this has to be the case, as similar species with radically different life spans exist in the wild. Compare mice with naked mole-rats, for example, a nine-fold difference in life expectancy. In practice, I suspect that engineering human cellular metabolism to this degree is a far future prospect, however. The advantage of the damage repair approach is that it does seem to offer goals that can be achieved in the near future, without a full understanding of cellular biochemistry, and which will achieve meaningful gains in life span and reduction in the burden of age-related disease.

Exploring juventology: unlocking the secrets of youthspan and longevity programs

The paradigm of longevity programs opens up new vistas for understanding interventions that extend lifespan without instigating adverse effects. While traditional aging research has often fixated on combating free radicals and oxidative stress, juventology suggests that the most effective pro-longevity interventions induce alternate survival phases. The exploration of longevity programs in model organisms reveals a complex network of cellular responses and adaptive strategies that challenge the somewhat conventional theories of aging. Especially, the interplay between nutrient availability and the activation of specific longevity programs is not just a passive response but instead highlights a sophisticated network of cellular events that over the course of the lifespan can result in a healthier aging phenotype and increased longevity. In E. coli, Saccharomyces cerevisiae, and C. elegans, starvation, the most severe form of dietary restriction, causes a major lifespan extension.

Juventology is fundamentally different from "aging-centered" theories of aging for two reasons: (1) alternative lifespan programs, such as those entered in response to starvation, can be independent (or are at least partially independent) of aging itself. As an example, one could visualize the use of target-specific pharmaceuticals or systemically broader acting periodic fasting intervals modulate the mTor-S6K and PKA pathways, which in turn can promote regeneration and rejuvenation. Notably, this can be achieved even in an organism with a high rate of aging. Thus, even in an accelerated aging phenotype, a longer healthspan and lifespan may be accomplished by periodically activating regenerative and rejuvenating processes. (2) Juventology shifts the focus from an "old or older age" paradigm characterized by high degrees of dysfunction and subsequent high morbidity and mortality, instead to the period in life during which both morbidity and mortality are very low and only difficult to detect.

Diseases in humans are generally rare before the (biological) age 40, but comorbidities are common after age 65, yet no specific field of science is focusing on how evolution resulted in a program that is extremely efficient in preventing disease for the first 40 years of life and how that program may be modulated and extended by dietary, pharmacological, or other interventions. On the one hand, developmental biology focuses on the biological process from embryo to (young) adult stage and generally does not include this important field. On the other hand, biogerontology the biological basis of aging and age-related diseases. Thus, juventology presents a complementary field to both gerontology and developmental biology that focuses on the period of organismal life when the force of natural selection is high and body functions remain maximized.

Periodic fasting and calorie restriction promote cells to enter into a stress resistance state which is characterized by the activation of cell protection, regeneration, and rejuvenation processes. Across multiple species, these protective and regenerative mechanisms are activated in part by the down-regulation of growth hormone, IGF-1, mTor-S6K, and PKA signaling cascades, which in turn induces the extension of healthspan. Because these states have evolved to withstand periods of extreme nutrient starvation, they can be viewed as alternative longevity programs activated to maintain cellular "youthspan" until resources that promote proliferative processes become available again. Here, we propose that these juventology-based approaches provide complementary strategies to the classic biogerontology approaches to focus on the earlier (i.e., biologically younger) functional period while also studying the later progressively dysfunctional processes that affect health and longevity.

Researchers here demonstrate an approach to cell therapy for an injured heart that produces lesser degrees of abnormal function than prior efforts. There has been some concern that delivering new cells to the heart to spur greater regeneration will disrupt the electrical regulation of heartbeats, as animal studies suggested an unacceptable risk of arrhythmia following treatment. This work still makes use of cardiomyocytes generated from induced pluripotent stem cells, already accomplished by a number of other groups, but differences in the details of the approach appear to make a positive change in the outcome.

In a recent study, a research team tested a new strategy for regenerative heart therapy that involves injecting 'cardiac spheroids' derived from human induced pluripotent stem cells (HiPSCs) into monkeys with myocardial infarction. First, the team verified the correct reprogramming of HiPSCs into cardiomyocytes. They observed, via cellular-level electrical measurements, that the cultured cells exhibited potential patterns typical of ventricular cells. The cells also responded as expected to various known drugs. Most importantly, they found that the cells abundantly expressed adhesive proteins such as connexin 43 and N-cadherin, which would promote their vascular integration into an existing heart. Afterwards, the cells were transported from the production facility. The cardiac spheroids, which were preserved at 4°C in standard containers, withstood the four-hour journey without problem. This means that no extreme cryogenic measures would be needed when transporting the cells to clinics, which would make the proposed approach less expensive and easier to adopt.

Finally, the monkeys received injections of either cardiac spheroids or a placebo directly into the damaged heart ventricle. During the observation period, the researchers noted that arrythmias were very uncommon, with only two individuals experiencing transient tachycardia (fast pulse) in the first two weeks among the treatment group. Through echocardiography and computed tomography exams, the team confirmed that the hearts of monkeys that received treatment had better left ventricular ejection after four weeks compared to the control group, indicating a superior blood pumping capability. Histological analysis ultimately revealed that the cardiac grafts were mature and properly connected to pre-existing existing tissue. "The favorable results obtained thus far are sufficient to provide a green light for our clinical trial. We are already employing the same cardiac spheroids on patients with ischemic cardiomyopathy."

Link: https://www.shinshu-u.ac.jp/english/topics/2024/04/using-stem-cell-deri.html

While researchers here focus specifically on stair climbing as a form of physical activity to compare against risk of mortality in later life, there are any number of other studies that focus on activity more generally, or on other forms of moderate to vigorous exercise. The consensus across epidemiological studies is that physical activity correlates with reduced mortality. Animal studies have been used to demonstrate that the exercise in fact causes that reduced mortality, and it is reasonable to consider that the same is true in humans.

Cardiovascular disease is largely preventable through actions like exercise. However, more than one in four adults worldwide do not meet recommended levels of physical activity. Stair climbing is a practical and easily accessible form of physical activity which is often overlooked. This study investigated whether climbing stairs, as a form of physical activity, could play a role in reducing the risks of cardiovascular disease and premature death.

The authors collected the best available evidence on the topic and conducted a meta-analysis. Studies were included regardless of the number of flights of stairs and the speed of climbing. There were nine studies with 480,479 participants in the final analysis. The study population included both healthy participants and those with a previous history of heart attack or peripheral arterial disease. Ages ranged from 35 to 84 years old and 53% of participants were women.

Compared with not climbing stairs, stair climbing was associated with a 24% reduced risk of dying from any cause and a 39% lower likelihood of dying from cardiovascular disease. Stair climbing was also linked with a reduced risk of cardiovascular disease including heart attack, heart failure, and stroke.

Link: https://www.eurekalert.org/news-releases/1042193

Atherosclerosis is the growth of fatty lesions in blood vessel walls, ultimately leading to a heart attack or stroke when an unstable lesion ruptures. Atherosclerosis is primarily a condition of macrophage dysfunction, in which these cells fail to keep up with their task of removing excess cholesterol from blood vessel walls in order to return it to to the bloodstream for transport back to the liver. The local excess of cholesterol is largely the proximate cause of this macrophage dysfunction, so as the amount of cholesterol grows, macrophages become ever less capable of dealing with it. They die, adding their mass to the lesion, while signaling for reinforcements that will suffer the same fate.

That said, this is a description of how atherosclerosis progresses once it gets started. How do the initial small excesses of cholesterol form in the first place? Most of the underlying root causes of aging are involved in the growing inability of macrophages to keep up with the task of cholesterol transport. Further, altered behavior of other cell populations with advancing age, in the liver and blood vessel walls, may be capable of disrupting cholesterol transport from the liver to the rest of the body, leading to excess deposits in blood vessels. In today's open access paper, researchers focus in on the age-related decline in mitochondrial function in the context of atherosclerosis: would improving mitochondrial function help?

Effects of mitochondrial dysfunction on cellular function: Role in atherosclerosis

Atherosclerosis is the basis of a large proportion of fatal cardiovascular events, and a significant number of cardiovascular-related deaths can be attributed to the rupture of atherosclerotic plaques. Thinning of the covered fibrous cap formed by vascular smooth muscle cells (VSMCs) results in cap rupture and erosion, which is responsible for the majority of cardiovascular-related deaths from myocardial infarction and stroke. Atherosclerosis is an age-associated disorder; however, with the development of non-invasive diagnostic methods and the accumulation of knowledge in postmortem research, asymptomatic lesions have been described in young adults, suggesting that atherosclerosis is a chronic disease that develops at a much younger age than previously thought.

Atherosclerosis is now widely accepted to begin with endothelial dysfunction and lipid deposits, which progress through macrophage infiltration. In atherosclerosis-prone areas, the chronic inflammatory response and impaired lipoprotein metabolism are among the major contributors to atherosclerotic lesion formation. The first idea linking mitochondria to atherosclerosis was reported in 1970, but it is only recently that increasing evidence has highlighted the key role of mitochondrial dysfunction in the pathogenesis of atherosclerosis. Mitochondrial dysfunction can induce high levels of oxidative stress and high rates of apoptosis, which can cause endothelial dysfunction and increase the vascular disease burden. The increase in reactive oxygen species (ROS) production in mitochondria, accumulation of mitochondrial DNA damage, and progressive respiratory chain dysfunction are all related to atherosclerosis.

Mitochondrial dysfunction is believed to result in an increase in reactive oxygen species, leading to oxidative stress, chronic inflammation, and intracellular lipid deposition, all of which can contribute to the pathogenesis of atherosclerosis. Critical cells, including endothelial cells, vascular smooth muscle cells, and macrophages, play an important role in atherosclerosis. Mitochondrial function is also involved in maintaining the normal function of these cells. To better understand the relationship between mitochondrial dysfunction and atherosclerosis, this review summarizes the findings of recent studies and discusses the role of mitochondrial dysfunction in the risk factors and critical cells of atherosclerosis.

The author of this paper is an advocate for programmed aging. This is the view that degenerative aging is actively selected by evolutionary processes, perhaps because it helps to reduce the risk of runaway population growth, or perhaps because aging species better adapt to ecological change, rather than being a side-effect of selection effects focused on early life reproductive success that tend to produce systems that accumulate damage to fail over time. In some programmed aging views, epigenetic change is close to being the root cause of aging, being the implementation of an evolutionarily selected program. It is interesting to see an outline of perceived challenges in epigenetic clock development from the programmed aging viewpoint, to contrast with the challenges seen by other researchers, which are focused on the lack of understanding of how specific epigenetic changes reflect underlying damage and dysfunction.

Late in life, the body is at war with itself. There is a program of self-destruction (phenoptosis) implemented via epigenetic and other changes. I refer to these as type (1) epigenetic changes. But the body retains a deep instinct for survival, and other epigenetic changes unfold in response to a perception of accumulated damage (type (2)).

In the past decade, epigenetic clocks have promised to accelerate the search for anti-aging interventions by permitting prompt, reliable, and convenient measurement of their effects on lifespan without having to wait for trial results on mortality and morbidity. However, extant clocks do not distinguish between type (1) and type (2). Reversing type (1) changes extends lifespan, but reversing type (2) shortens lifespan. This is why all extant epigenetic clocks may be misleading.

Separation of type (1) and type (2) epigenetic changes will lead to more reliable clock algorithms, but this cannot be done with statistics alone. New experiments are proposed. Epigenetic changes are the means by which the body implements phenoptosis, but they do not embody a clock mechanism, so they cannot be the body's primary timekeeper. The timekeeping mechanism is not yet understood, though there are hints that it may be (partially) located in the hypothalamus. For the future, we expect that the most fundamental measurement of biological age will observe this clock directly, and the most profound anti-aging interventions will manipulate it.

Link: https://doi.org/10.1134/S0006297924020135

The progressive dysfunction of sweat glands in the skin is probably not high on the list of items that people think about in the context of degenerative aging, at least not until they experience it. A reduced capacity of sweat glands leads to heat intolerance, and it is one of the contributing causes of the raised mortality rate among the elderly in heat waves. Here, researchers examine some of the biochemistry of sweat gland cells in aging mice. They focus in on a number of proteins that may turn out to be viable targets for drugs to force sweat glands in aged skin back to a more youthful degree of function. It is a long road from fundamental investigations of this sort to that outcome, however.

Evaporation of sweat on the skin surface is the major mechanism for dissipating heat in humans. The secretory capacity of sweat glands (SWGs) declines during aging, leading to heat intolerance in the elderly, but the mechanisms responsible for this decline are poorly understood. We investigated the molecular changes accompanying SWG aging in mice, where sweat tests confirmed a significant reduction of active SWGs in old mice relative to young mice.

We first identified SWG-enriched messenger RNAs (mRNAs) by comparing the skin transcriptome of Eda mutant Tabby male mice, which lack SWGs, with that of wild-type control mice by RNA-sequencing analysis. This comparison revealed 171 mRNAs enriched in SWGs, including 47 mRNAs encoding 'core secretory' proteins such as transcription factors, ion channels, ion transporters, and trans-synaptic signaling proteins. Among these, 28 SWG-enriched mRNAs showed significantly altered abundance in the aged male footpad skin, and 11 of them, including Foxa1, Best2, Chrm3, and Foxc1 mRNAs, were found in the 'core secretory' category.

Consistent with the changes in mRNA expression levels, immunohistology revealed that higher numbers of secretory cells from old SWGs express the transcription factor FOXC1, the protein product of Foxc1 mRNA. In sum, our study identified mRNAs enriched in SWGs, including those that encode core secretory proteins, and altered abundance of these mRNAs and proteins with aging in mouse SWGs.

Link: https://doi.org/10.18632/aging.205776